Systemic transforming growth factor-β1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice

Xunrong Luo, Hua Yang, Il Soo Kim, Fludd Saint-Hilaire, Dolca A. Thomas, Bishnu P. De, Engin Ozkaynak, Thangamani Muthukumar, Wayne W. Hancock, Ronald Crystal, Manikkam Suthanthiran

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background. Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)- β1, we investigated whether systemic TGF-β1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice. Methods. We used site-directed mutagenesis to create cysteine to serine mutation at sites 224 and 226 and constructed a replication deficient adenovirus (Ad) vector encoding active form of human TGF-β1 (Ad-hTGF- β1). Overtly diabetic NOD mice received intravenous injection of Ad-hTGF-β1. Seven to 14 days after the injection, the mice received transplants with 500 syngeneic islets under the kidney capsule. Islet-graft survival and regeneration of endogenous beta-cell function were examined. Results. Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF-β1 therapy prolonged survival of islet grafts. Islet grafts from treated mice showed well-preserved islets with a peri-islet infiltrate primarily of CD4+ T cells and expression of CD25 and Foxp3. Systemic TGF-β1 gene therapy was associated with islet regeneration in the native pancreas. Native pancreas of treated mice revealed islets staining strongly for insulin. Similar to what was found in the syngeneic islet graft, there were well-demarcated peri-islet infiltrates that were positive for CD4, TGF-β1, and Foxp3. Conclusions. Our data demonstrate that systemic TGF-β1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice.

Original languageEnglish
Pages (from-to)1091-1096
Number of pages6
JournalTransplantation
Volume79
Issue number9
DOIs
Publication statusPublished - 15 May 2005
Externally publishedYes

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Self Tolerance
Inbred NOD Mouse
Transforming Growth Factors
Genetic Therapy
Regeneration
Adenoviridae
Transplants
Pancreas
Graft Survival
Autoimmunity
T-Lymphocytes
Site-Directed Mutagenesis
Type 1 Diabetes Mellitus
Islets of Langerhans
Intravenous Injections
Serine
Capsules
Cysteine
Insulin
Staining and Labeling

Keywords

  • Ad-TGF-β1
  • Islet regeneration
  • NOD mice
  • Regulatory T cells

ASJC Scopus subject areas

  • Transplantation

Cite this

Systemic transforming growth factor-β1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. / Luo, Xunrong; Yang, Hua; Kim, Il Soo; Saint-Hilaire, Fludd; Thomas, Dolca A.; De, Bishnu P.; Ozkaynak, Engin; Muthukumar, Thangamani; Hancock, Wayne W.; Crystal, Ronald; Suthanthiran, Manikkam.

In: Transplantation, Vol. 79, No. 9, 15.05.2005, p. 1091-1096.

Research output: Contribution to journalArticle

Luo, Xunrong ; Yang, Hua ; Kim, Il Soo ; Saint-Hilaire, Fludd ; Thomas, Dolca A. ; De, Bishnu P. ; Ozkaynak, Engin ; Muthukumar, Thangamani ; Hancock, Wayne W. ; Crystal, Ronald ; Suthanthiran, Manikkam. / Systemic transforming growth factor-β1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. In: Transplantation. 2005 ; Vol. 79, No. 9. pp. 1091-1096.
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abstract = "Background. Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)- β1, we investigated whether systemic TGF-β1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice. Methods. We used site-directed mutagenesis to create cysteine to serine mutation at sites 224 and 226 and constructed a replication deficient adenovirus (Ad) vector encoding active form of human TGF-β1 (Ad-hTGF- β1). Overtly diabetic NOD mice received intravenous injection of Ad-hTGF-β1. Seven to 14 days after the injection, the mice received transplants with 500 syngeneic islets under the kidney capsule. Islet-graft survival and regeneration of endogenous beta-cell function were examined. Results. Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF-β1 therapy prolonged survival of islet grafts. Islet grafts from treated mice showed well-preserved islets with a peri-islet infiltrate primarily of CD4+ T cells and expression of CD25 and Foxp3. Systemic TGF-β1 gene therapy was associated with islet regeneration in the native pancreas. Native pancreas of treated mice revealed islets staining strongly for insulin. Similar to what was found in the syngeneic islet graft, there were well-demarcated peri-islet infiltrates that were positive for CD4, TGF-β1, and Foxp3. Conclusions. Our data demonstrate that systemic TGF-β1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice.",
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AU - Luo, Xunrong

AU - Yang, Hua

AU - Kim, Il Soo

AU - Saint-Hilaire, Fludd

AU - Thomas, Dolca A.

AU - De, Bishnu P.

AU - Ozkaynak, Engin

AU - Muthukumar, Thangamani

AU - Hancock, Wayne W.

AU - Crystal, Ronald

AU - Suthanthiran, Manikkam

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